The overall goal of this Program Project is to understand molecular mechanisms regulating arteriogenesis that may be exploited as potential treatments for vasoocclusive cardiovascular diseases including coronary artery disease, peripheral arterial disease and cerebrovascular disease. We have assembled a multidisciplinary team of highly accomplished PIs with diverse backgrounds (cardiology, cell biology, biomechanical engineering, pharmacology) to investigate key molecular events that lead to development and growth of arterial vasculature. The in-depth understanding of these mechanisms can then be parlayed into development of novel therapeutic modalities for this important group of cardiovascular diseases. Together, our studies will define the key events leading to arterial vessel growth and will lead to the development of new therapies. PPG Aims are: Aim 1. Elucidate how ERK signaling controls arteriogenesis (Project 1). Aim 2. Unravel the role of the miR 17-92 cluster in controlling arteriogenesis and its regulation and interaction with ERK signaling (Project 2 Aim 3. Determine how fluid shear stress and changes in the extracellular matrix activate ERKs and other signaling pathways that mediate arteriogenesis, and identify restriction points that impair arteriogenesis in disease (Project 3). Relevance to Public Health: Coronary artery disease and peripheral artery disease are major causes of illness and death in developed nations. Poor arteriogenesis is a critical determinant of these diseases and in patients? recovery after myocardial infarction. This application proposes to elucidate the signaling network that governs flow-dependent vessel remodeling and test two new directions for improving arteriogenesis. These studies include testing whether activating an arteriogenic signaling pathway improves arteriogenesis in disease models. They have the potential to identify new targets and new reagents for therapy, as well as to achieve a deeper understanding of the fundamental biology that will form the basis for future studies.